Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

• This invention relates to the use of adinazolam and some other 1-substituted-triazolo-benzodiazepines as antipsychotic drugs, particularly as antischizophrenic drugs.
• Adinazolam is now an accepted generic name for 8-chloro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, and is described and claimed among other compounds in U.S. Pat. No. 4,250,094.
• Adinazolam and some other 1-amino-triazolo-benzodiazepines have undergone preliminary testing in their in vivo 3 H-Spiroperidol binding system test in animals, which test is highly selective for antipsychotic active drug compounds. Test results with adinazolam were weak but suggested antipsychotic-like activity. A variety of other compounds of this invention also showed activity in this test.
• adinazolam and certain other 1-amino-group-triazolo-benzodiazepine compounds have been found to be active in the 3 H-Spiroperidol binding test in animals, indicating their possible usefulness as antipsychotic, including antischizophrenic, drugs.
• adinazolam in human patients suffering from forms of intractable psychosis or schizoaffective illnesses, treatment of the patients with small, but effective and safe dosage amounts of adinazolam resulted in improved symptoms of schizophrenia and affective improvement.
• R 2 , R 3 , R 4 and R 5 are hydrogen, C 1 to C 3 -alkyl, fluoro, chloro, bromo, nitro, or trifluoromethyl, and
• Y is selected from the group consisting of ##STR2## wherein in amino-group (a) above R is hydrogen, C 1 to C 3 -alkyl or B-hydroxyethyl; in amino groups (b) and (c), R' and R" are independently hydrogen or C 1 or C 3 -alkyl, and R o is hydrogen, or C 1 to C 2 -alkyl, or a pharmacologically acceptable salt thereof, are useful and effective in treating human patients suffering psychoses, including schizophrenic, illnesses.
• Examples of compounds of this type include:
• Pharmaceutically acceptable acid addition salts of the above compounds are prepared by reacting the free base of a compound of Formula (I) with a stoichiometric amount of an acid, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, butyric acid, lactic acid, citric acid, succinic acid, benzoic acid, methanesulfonic acid, salicyclic acid, pamoic acid, phthalic acid, cyclohexanesulfamic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, and the like.
• an acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, butyric acid, lactic acid, citric acid, succinic acid, benzoic acid, methanesulfonic acid, salicyclic acid, pamoic acid, phthal
• This invention relates also to pharmaceutical dosage unit forms for systemic administration (oral and parenteral and rectal administration) for treating psychotic and schizophrenic humans.
• dosage unit form refers to physically discrete units suitable as unitary dosages for mammalian subjects, each unit containing a predetermined quantity of the essential active ingredient, i.e., a compound (I) or a pharmaceutically acceptable acid addition salt thereof, calculated to produce the desired effect, in combination with the required pharmaceutical means which adapt the said ingredient for systemic administration.
• Examples of dosage unit forms in accordance with this invention are tablets, capsules, orally administered liquid preparations in liquid vehicles, sterile preparations in liquid vehicles for intramuscular and intravenous administration, suppositories, and sterile dry preparations for the extemporaneous preparation of sterile injectable preparations in a liquid vehicle.
• Solid diluents or carriers for the solid oral pharmaceutical dosage unit forms are selected from the group consisting of lipids, carbohydrates, proteins and mineral solids, for example, starch, sucrose, kaolin, di-calcium phosphate, gelatin, acacia, corn syrup, corn starch, talc and the like.
• Capsules both hard and soft, are formulated with conventional diluents and excipients, for example, edible oils, talc, calcium carbonate, calcium stearate and the like.
• Liquid preparations for oral administration are prepared in water or aqueous or nonaqueous vehicles which advantageously contain suspending agents, such as for example, ethanol, sodium carboxymethylcellulose, acacia, polyvinyl pyrrolidone, polyvinyl alcohol and the like. In the instance of injectable forms, they must be sterile and must be fluid to the extent that easy syringeability exists.
• Such preparations must be stable under the conditions of manufacture and storage, and ordinarily contain in addition to the basic solvent or suspending liquid, preservatives in the nature of bacteriostatic and fungistatic agents, for example, parabens, chlorobutanol, benzyl alcohol, phenol, thimerosal and the like.
• preservatives in the nature of bacteriostatic and fungistatic agents, for example, parabens, chlorobutanol, benzyl alcohol, phenol, thimerosal and the like.
• isotonic agents for example, isotonic amounts of sugars or sodium chloride.
• Carriers and vehicles include vegetable oils, ethanol and polyols, for example, glycerol, propylene glycol, liquid polyethylene glycol and the like.
• any solid preparations for subsequent extemporaneous preparation of sterile injectable preparations are sterilized, preferably by exposure to a sterilizing gas, such as, for example, ethylene oxide.
• a sterilizing gas such as, for example, ethylene oxide.
• a daily dose of 1 to 700 mg is indicated, preferentially 10 to 200 mg; in units of two or three or four subdivided doses, and the exact amount is adjusted based on the weight, age and condition of the patient.
• the pharmaceutical dosage unit forms are prepared in accordance with the preceding general description to provide from about 0.5 mg to about 100 mg of the essential active ingredient per dosage unit form.
• the amount of the essential active ingredient provided in the pharmaceutical dosage unit forms is based on the finding that the effective amount of adinazolam, a representative example of the compounds of the invention and acid addition salts thereof, for obtaining an antipsychotic effect in humans is within a range from about 0.01 mg/kg to about 10 mg/kg, preferably 0.06 to 1.0 mg/kg.
• the active ingredients of this invention can also be compounded in combination with other ingredients.
• the amount of such other active ingredients is to be determined with reference to the usual dosage of each such ingredient.
• these active compounds can be combined with hypotensive agents such as ⁇ -methyldopa (100-250 mg); with diuretics such as hydrochlorothiazide (10-50 mg); tranquilizers such as meprobamate (200-400 mg), diazepam (2-10 mg), muscle relaxants, such as carisoprodol (200-400 mg).
• mice Male ICR mice weighing 20-22 g were used. The mice were pretreated with test drug solutions or vehicle mixtures subcutaneously one hour before injection of 66 micro Curie/kg, in 0.2 ml, of 3 H-Spiroperidol (specific activity of 29.9 Curie per mmole). The test drug compounds were dissolved in saline, 1M citric acid in water or 33% propylene glycol in water solution, and then diluted to volume with saline.
• the animals were dosed with the 3 H-Spiroperidol solution at 66 micro-Curie/kg in 0.2 ml, by the subcutaneous route.
• the animals were sacrificed 2 hours later and sections of the brains of the mice were removed with striata and septum and some adjacent cortex.
• the tissues were weighed after freezing on dry ice and dissolved in 1 ml of Protosol overnight at 35° C.
• the Protosol was neutralized with 80 ⁇ l of 6N hydrochloric acid and 15 ml of ACS scintillation fluid was added. All samples were then counted in a liquid scintillation counter.
• CPM counts per minute
• adinazolam was given for two days at a dosage of 5 mg bid (twice a day) the first day and 5 mg tid (three times a day) the second day to a human schizoaffective patient suffering moodcongruent delusions and persecutory auditory hallucinations which had been refractory to four months of therapy with a tricyclic antidepressant and stelazine.
• the clinician serving the patient found a remarkable approximately fifty percent (50%) improvement in the patient's condition over the two days of treatment with adinazolam.
• adinazolam in the treatment of human patients for psychotic, including schizophrenic, disorders in the absence of depression are in progress. Five patients have been treated and all experienced moderate or marked improvement. Patients are being maintained on dosages of from 2.5 to 20 mg. of adinazolam qid (four times a day). One patient showed a dramatic effect when medication was unintentionally withdrawn for 24 hours. The patient reverted to a psychotic condition during this 24 hour period. Following this period, when adinazolam therapy was reinitiated in the morning the patient became lucid again that same day.
• adinazolam possesses important safety advantages over known standard antipsychotic drugs: lack of extrapyramidal side effects, lack of sedation effect, lack of tardive diskinesia, and lack of serum prolactin elevation. In one patient extrapyramidal side effects persisting from previous medication disappeared with adinazolam therapy.
• Elevations in striatal homovanillic acid may be taken as an indicator of the propensity of an antipsychotic drug to induce extrapyramidal side effects and tardive dyskinesia.
• Benzodiazepines reverse this HVA elevating effect, Arch. Pharmacol., 294, pp. 1-7, "Interaction of Benzodiazepines with Neuroleptics at Central Dopamine Neurons" by H. H. Keller et al.
• benzodiazepines may also reverse extra pyramidal side effects and tardive dyskinesia as well.
• Neuroendocrine effects of antipsychotic drugs are a very predominant side effect, especially prolactin elevations.
• adinazolam had no apparent elevating effect on serum prolactin levels in the open-label depression studies.
• four human patients (2 males; 2 females) with elevated prolactin levels at the introductory screening physicals, the prolactin levels in all four patients normalized during treatment with adinazolam. (Three of the patients had been treated recently with a phenothiazine or amoxapine).

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• Health & Medical Sciences (AREA)
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• Neurology (AREA)
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• Psychiatry (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

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• 1983
  • 1983-02-18 US US06/467,691 patent/US4472397A/en not_active Expired - Fee Related
• 1984
  • 1984-01-03 ZA ZA8430A patent/ZA8430B/xx unknown
  • 1984-01-16 DE DE19843401290 patent/DE3401290A1/de not_active Withdrawn
  • 1984-01-25 AU AU23770/84A patent/AU560215B2/en not_active Ceased
  • 1984-02-13 PH PH30234A patent/PH20776A/en unknown
  • 1984-02-15 JP JP59027990A patent/JPS59157022A/ja active Pending
  • 1984-02-16 IT IT19659/84A patent/IT1175942B/it active
  • 1984-02-17 EP EP84301048A patent/EP0117140A1/fr not_active Withdrawn
  • 1984-02-17 BE BE0/212415A patent/BE898943A/fr not_active IP Right Cessation

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Non-Patent Citations (49)

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